The present invention involves a novel use for natural and synthetic vanilloid compounds. The following are non-limiting examples of such vanilloid compounds, and references in which they are disclosed; all of the following references are hereby incorporated herein in their entirety by reference: capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide) and "synthetic" capsaicin (N-vanillylnonanamide) in U.S. Pat. No. 4,313,958, LaHann, issued Feb. 2, 1982; capsaicin in Yaksh, et al, Science, 206, pp 481-483 (1979); capsaicin in Jancso, et al, Naunyn-Schmiedeberg's Arch. Pharmacol., Vol. 311, pp 285-288 (1980); capsaicin in Holzer et al, Eur. J. Pharm. Vol. 58, pp. 511-514 (1979); 3-hydroxyacetanilide in U.S. Pat. No. 4,238,508, Nelson, issued Dec. 9, 1980; hydroxyphenylacetamides in European Patent Application 0089710, LaHann, et al, published Sep. 28, 1983; N-vanillyl sulfonamides in U.S. Pat. No. 4,401,663, Buckwalter, et al, issued Aug. 30, 1983; hydroxyphenyl-acetamides in U.S. Pat. No. 4,424,205, LaHann, et al, issued Jan. 31, 1984; N-(3- or 4-hydroxy or 3,4-dihydroxybenzyl) carbamates in U.S. Pat. No. 4,443,473, Buckwalter, et al, issued Apr. 17, 1984; N-[(substituted phenyl) methyl]-cis-monounsaturated alkenamides in U.S. Pat. No. 4,493,848, LaHann, et al, issued Jan. 15, 1985; N-(3-methoxy-4-hydroxybenzyl and phenyl) ureas and thioureas in U.S. Pat. No. 4,460,602, Buckwalter, et al, issued Jul. 17, 1984; N-vanillylureas in European Patent Application 0068590, Buckwalter, et al, published Jan. 5, 1983; N-[(substituted phenyl)methyl]alkynamides in U.S. Pat. No. 4,532,139, Janusz, et al, issued Jul. 30, 1985; methylene substituted N-[(substituted phenyl)methyl]alkanamides in U.S. Pat. No. 4,544,668, Janusz, et al, issued Oct. 1, 1985; N-[(substituted phenyl)methyl]-diunsaturated amides in U.S. Pat. No. 4,544,669, LaHann, et al, issued Oct. 1, 1985; monoalkenamides in U.S. Pat. No. 4,564,633, LaHann, et al, issued Jan. 14, 1986; substituted phenylacetic acid esters in British Patent Specification 2,168,974, Loomans, et al, published Jul. 2, 1986; N-(substituted alkyl)alkanamides and thioamides in British Patent Specification 2,168,976, Loomans, et al, published Jul. 2, 1986; substituted aromatic-araalkanamides in British Patent Specification 2,168,975, Janusz et al, published Jul. 2, 1986; and beta-aminoethyl-substituted phenyl compounds in European Patent Application No. 282,127, Gardner, et al., published Sep. 14, 1988.
Vanilloid compounds have been generally disclosed in the above references to have analgesic, anti-irritant and anti-inflammatory activity.
The use of capsaicin to affect the nervous system of humans and other animals, and to treat the pain associated with herpes zoster infections, has been disclosed in a number of references. Handwerker, H. O., U. Holzer-Petsche, Ch. Heym and E. Welk, "C-Fibre Functions After Topical Application of Capsaicin to a Peripheral Nerve and after Neonatal Capsaicin Treatment", Antidromic Vasodilation and Neurogenic Inflammation: Satellite Symposium of the 29th International Congress of Physiological Sciences, Newcastle, Australia, 1983, Edited by Chahl, L. A., J. Szolcsanyi, and F. Lembeck, Akademiai Kiado, Budapest, (1984) pp. 57-78, discloses that after repeated capsaicin application, nociceptors become desensitized to subsequent chemical and presumably also heat stimuli. Taylor, D. C. M., Fr.-K. Pierau and J. Szolcsanyi, "The Effect of Capsaicin on Axoplasmic Transport in a Rat Peripheral Nerve", Antidromic Vasodilation and Neurogenic Inflammation: Satellite Symposium of the 29th International Congress of Physiological Sciences, Newcastle, AUstralia, 1983, Edited by Chahl, L. A., Szolcsanyi, J. and F. Lembeck, Akademiai Kiado, Budapest, (1984), pp. 165-171, discloses that systemic capsaicin decreased substance P levels in the dorsal root ganglia and the spinal cord, and that nerve growth factor (NGF) transport in the peripheral nerve may be blocked by systemic capsaicin. Jancso, G., F. Obal, Jr., I. Toth-Kasa, M. Katona and S. Husz, "The Modulation of Cutaneous Inflammatory Reactions by Peptide-Containing Sensory Nerves", International Journal of Tissue Reactions, Vol. VII, (1985), pp. 449-457, discloses a possible role of the nervous system to the mechanisms of inflammation through peptide containing sensory nerves. While rats treated neonatally with capsaicin showed complete abolishment of neuro-genic inflammation, repeated topical application of the skin with capsaicin (local desensitization) abolished the neurogenic inflammatory response for several days, along with strongly reduced chemical pain sensitivity and elevated thresholds for warmth and heat pain sensations. Local capsaicin desensitization of the skin prevented whealing, flare and itch in patients with acquired cold and heat urticaria. Jancso, G., S. Husz and N. Simon, "Impairment of Axon Reflex Vasodilatation after Herpes Zoster", Clinical and Experimental Dermatology, Vol. 8, (1983), pp. 27-31, discloses an effect on chemosensitive primary sensory neurons and impairment of axon reflex vasodilatation in skin vessels following herpes zoster infection and the possible mechanisms by which herpes zoster may effect the vascular reactions of the skin.
Capsaicin has been disclosed as an effective compound for the treatment of severe pain associated with herpes zoster infections. Bernstein, J. E., "Capsaicin in the Treatment of Dermatologic Disease", Cutis, Vol. 39, (April 1987), pp. 352-353, discloses use of capsaicin in the possible treatment of post-herpetic neuralgia and psoriasis. Bernstein, J. E., D. R. Bickers, M. V. Dahl, Jay Y. Roshal, "Treatment of Chronic Postherpetic Neuralgia with Topical Capsaicin", Journal of the American Academy of Dermatoloqy, Vol. 17, (1981), pp. 93-96, discloses topical application of capsaicin to patients suffering from postherpetic neuralgia as a possible approach for alleviating postherpetic neuralgia and other syndromes characterized by severe localized pain. U.S. Pat. No. 4,536,404, Bernstein, issued Aug. 20, 1985, discloses a method for treating post-herpetic neuralgia due to herpes zoster wherein an effective amount of capsaicin is topically applied to the area affected with herpes zoster to relieve the symptoms of post-herpetic neuralgia.
Capsaicin's effect on the neurogenic response on the skin and in sensory transmission in mice with herpes simplex infections is disclosed in the following two references. Harbour, D. A., T. J. Hill and W. A. Blyth, "Recurrent Herpes Simplex in the Mouse: Inflammation in the Skin and Activation of Virus in the Ganglia Following Peripheral Stimulation", Journal of General Virology, Vol. 64, (1983), pp. 1491-1498, discloses chemical stimuli to the skin which induce recurrent herpes simplex virus disease and reactivation of infectious virus in the ganglia. Capsaicin is injected subcutaneously prior to injection of the mice with dye to help determine the effect of mediators on the permeability of blood vessels. Ljungdahl, A., K. Kristensson, J. M. Lundberg, E. Lycke, B. Svennerholm and R. Ziegler, "Herpes Simplex Virus Infection in Capsaicin-Treated Mice", Journal of the Neurological Sciences, Vol. 72, (1986), pp. 223-230, discloses that capsaicin injected subcutaneously prior to herpes simplex virus (HSV) inoculation of the snouts of four day old (neonatal) mice, reduced the mortality rate of HSV-infected mice.
Herpes Zoster Infections
Herpes zoster infections are caused by the varicella-zoster virus (VZV), the etiologic agent of the conditions commonly known as shingles, zona and acute posterior ganglionitis.
VZV infections usually cause severe pain and exhibit large groups of lesions distributed along the course of a sensory nerve. Vesicular eruption causes neuralgic pain in the cutaneous area supplied by the peripheral sensory nerves. The vesicular eruptions of herpes zoster are often activated by local lesions involving the posterior root ganglia, systemic diseases such as Hodgkins, and immunosuppressive therapy.
VZV is also the causative agent in chicken pox. Later herpes zoster infections (or shingles outbreaks) are most common after the age of fifty. Crops of vesicles form on an erythemateous base and follow the sensory distribution of one or more posterior root ganglia. The sensory zone on the skin that is affected is usually hyperaesthetic with associated severe pain.
Postherpetic neuralgia is often seen in patients over 60 years of age following a vesicular eruption caused by VZV. Following the eruption, a syndrome of dermatologic rash and pain usually ensues. The rash generally resolves spontaneously in 2 to 3 weeks. The pain may continue and be severe. The treatment of postherpetic neuralgia has often been unsatisfactory and is essentially symptomatic, often requiring potent analgesics and tranquilizers. The postherpetic neuralgia associated with VZV infections may persist for months or years. The pain can be so intractable that it has been implicated in prolonged depression and even suicide. Not infrequently the pain is sufficiently severe and persistent that neurosurgical procedures may be employed in an effort to relieve the patient's discomfort.
Herpes zoster infections rarely recur in a patient (recurrence rate is less than 2%); one attack, generally associated with an outbreak of lesions in any one of numerous areas of the skin surface, usually confers immunity.